NIST Colloquium Series: Applied Click Chemistry: From Dyeing Cotton to Drug Discovery


[Music]>>Bill: Good morning
everyone and welcome to this year’s Christmas
Colloquium. When I invited Barry Sharpless
to give this talk, he asked me, you know, outside of the fact
that the colloquium’s going to be given in December,
what’s so special about it, and what’s so special about it
is the person introducing you is actually one of Santa’s Elves. And, I know you’ve
been introduced by some very very famous
people in the past, but this may be the
first time someone from the North Pole, like this. So, I wish you all a Merry
Christmas and Happy Holidays, and hope all goes well for
you this Christmas season. Barry Sharpless is our special
guest today and is going to give a talk about something that he is very passionate
about, and that’s Applied
Click Chemistry from dying cotton
to drug discovery. Barry Sharpless shared the
2001 Nobel Prize in Chemistry for his work on chirally
catalyzed oxidation reactions, and that was the same year
that [inaudible] Eric Cornell and Carl Wieman shared the
Nobel Prize in Physics. In fact, I told Barry
earlier, we were, many of us were gathered
right here in the auditorium and watched that ceremony
live, from Stockholm, so we didn’t realize it at the
time, but we watched you walk across the stage
at that time too. Incidentally, the other half
of the prize in Chemistry that year was for work on chirally catalyzed
hydrogenation reactions, and that was shared by William
Knowles of Monsanto Company and Ryoji Noyori of
Nagoya University in Japan. Barry’s work, the work
that he was recognized for makes it possible
to synthesize molecules, materials basically
with new properties. This has been especially useful,
I would say, over the last 10 to 20 years, in the
pharmaceutical industry for developing new antibiotics, anti-inflammatory drugs,
and heart medicines. Barry Sharpless grew
up in Philadelphia, went to Friends Central
High School in Haverford. And, during his high
school years, at times, his mind drifted into
dreams, I’m taking this now from his autobiography so,
so he knows about this, he wrote it himself, and so like
most teenagers, at the time, he had dreams, daydreams, but his dreams were a little
bit different, and no, they were not of chemistry. They were not of
catalyzed reactions; they were of the ocean,
and what we call the shore. I’m from Philadelphia too, and
in those days, everybody wanted to go to the shore, not,
here it’s the beach we go to, but we went to the shore. In fact, one of his great loves
is the ocean, it’s the rivers, lakes, he’s been an oarsman,
he’s worked in the summers on fishing boats in
the Atlantic Ocean, and he just loves the sea, and
it’s still one of his passions. He went to college at
Dartmouth College, and got his, started out actually as a
Pre-Med major and got exposed to organic chemistry in,
I guess, his second year, and though, “Oh, this is
really much more interesting than that other stuff.” And so, he majored in Chemistry. Went on to graduate school at Stanford University,
where he got his PhD. He stayed on an extra year
to do post-doc work there with JP Coleman, and he also
went to Harvard University for another year of post-doc,
this time with Conrad Block. He got into a tenure
track position at MIT, and spent the next 20 years
at MIT, except for a couple of years that he went back
to Stanford University to renew some of
his research there. Since 1990, he has been
back at the ocean, really, maybe that even some motivation for moving back to
the west coast. He’s at the Scripps
Research Institute, where he is the Keck Professor
of Chemistry and member of the Skaggs Institute
for Chemical Biology. Barry is best known for
discovering three reactions, which often have his
name attached to them. These are the catalytic
asymmetric epoxidation reaction, the dihydroxylation reaction, and the amino hydroxylation
reaction. The Noble Citation talks
about the epoxidation, the Sharpless epoxidation
reaction as follows, “Many scientists have identified
Sharpless’s epoxidation, discovered in 1980, as the most
important discovery in the field of synthesis over
the past 20 years.” At Scripps, he continues his,
really, career long search for useful new reactivity
and general methods for selectively controlling
chemical reactions. Click chemistry, he’s been, as
I said, passionately involved with since he started this
research, probably about five or six years ago, and this is,
you can hear about it today, it’s a set of powerful
selective reactions for rapidly synthesizing
new compounds. And he since told me by
now, he can hardly sleep. This is really such an exciting
thing, things are happening so quickly that, as I picked him
up at the hotel this morning, he was working on
some of this stuff. So, it’s really become
a passion. Obviously, he’s won
many awards, and prizes, became a National Academy
of Science Member in 1985, the King Faisal Prize
for Science in 1995, the Benjamin Franklin medal, from the Franklin
Institute in 2001. If any of you are from
Philadelphia, you know, your heart pounds when you go
back to the Franklin Institute, to actually be honored
with a Franklin Medal, and then he got the
Wolf Prize also in 2001. Just a quick story, because he
will probably won’t tell this story, but when he asked what
was the most exciting moment in all of these awards
and stuff, it wasn’t, it wasn’t the phone
call from Stockholm, it was actually a phone
call, when he became a Member of Academy of Sciences. And, the reason this
was so exciting was that he was actually giving
a lecture, at a conference, invited lecture, and the call
was answered by his wife, who was at his, his wife and
children were at the conference as well, and she was
in the hotel room. So, the person on the phone
said, “You know, you really, you really need to
tell him right away, this is really really
tremendously exciting, and quite an honor and all.” So, she finally said,
“Okay, I’ll do that.” So, the kids were little,
so she had to grab the kids and she went to the conference
and he was giving a lecture, and as he was giving
the lecture, he saw her and the children come walking
across the back of the room, and he became a little alarmed. So, he actually stopped his
lecture, and said to his wife, “You know, is there
anything wrong?” So, she must have shouted from
the back of the auditorium, “Well, nothing’s
wrong, we just came here to tell you’ve been
admitted as a Member of the National Academy
of Sciences.” [Laughter] Of course the whole place
roared, I mean, with claps and everything and this must
have been actually a very very touching moment for you, and I
hope you don’t mind my telling, sharing that story
with the staff here. So, without further
ado, can you join me in welcoming Barry Sharpless? [ Clapping ]>>Barry Sharpless: Thank
you Bill, I really, it’s been a pleasure,
he’s such a gentleman and fascinating fellow, and
I should have recognized him, he still has the accent,
but he, that story was, is actually pretty close
to the way it happened. The thing that really
was amazing to me, and this is a sign of the times
I think, right, I had no idea that George Buchi,
the late George Buchi, my sort of Swiss Professor,
father, and [inaudible], had nominated me for
the National Academy, in other words, this
came out of the blue. You know, today, I don’t
think many things come out of the blue like
that anymore. Nobody, you know, he was a
real gentlemen, European style, he went over, just
got my Secretary, told her get me some data,
and nominate, and a couple, you know, five years
later, you know, that doesn’t happen very often,
and George was a real gentleman, and so was Nelson Leonard,
who just passed away. They don’t seem to be replicating those
people, in our field. Okay, water is a big thing
in my life, as you heard, and mostly saltwater, actually, because I’m not really
interested in things that don’t have creatures. I’m looking for creatures. I gave up on microscopic. I look for molecule
creatures now, see, that, I don’t take pictures
anymore, I don’t go fishing, I still like being near
the ocean and walking, but I’m looking for creatures,
something I don’t know is there, that’s the metaphor,
coelacanths, that’s that article, it
was an autobiography, it was just the thing I wrote
for the Nobel thing, it wasn’t, my wife wrote it actually, she
knows more about me than I do. She told me, I was
looking for my coelacanths, so it’s called Coelacanths and
Catalysis, because, you know, we founded Coelacanths in
1938, that was our generation, everybody’s going into
the woods, thumbs up, we’re going to find the Getty,
we’re going to get Dinosaurs, it was, and the Japanese,
just like us, they loved monster movies and
anyway, anything was possible, it seems the world is less
optimistic these days. This is the, we went to
the Antarctic on this, one trip to South America for
a meeting, and that was in 19, I mean in 2004, with
the family, and I just, my son was taking pictures, and I just couldn’t believe
how many little krill, they’re about this big,
little shrimp like things, I guess they’re not good for
us to eat, with the shell, because they have a lot
of fluoride in them, but it’s a metaphor for how
rich life is on this planet. Down there, in the summer,
in the Arctic summer, Antarctic summers, there’s
just massive amounts of food in the water. So, the thing that really, I
guess I went to Quaker school, my father was from a Quaker
family, doing something useful, I always like George Hammond’s
old quote here, it says, “The most fundamental
lasting objective of synthesis is not
production of compounds, but production of properties.” There’s just too many compounds. Even little compounds, like
could be drugs, 500 [inaudible] or less and just have
the elements of drugs. There’s estimated to be 10 to
the 63 possible structures. And that’s like,
there are 10 to the, visible universe is
estimated to have 10 to the 80th Dalton
protons, so 10 to the, there’s not enough
carbon to make one of every one those little guys. There’s, we haven’t made any, we’ll never make
any, it’s impossible. We’d all have to make, I think,
10 to the 30th compounds today, for 10 to the 30th years,
grandfathers, children, everybody, 6 billion of us,
so we’ve got a problem here. I told you, I don’t have
any reference for structure, all I care about is function. I have to know structure,
structure is trivial though. I mean, you know, that s,
this is 19 something, 8, 2006, you don’t know the structure, you just tell somebody what
you know and don’t know, but the structure’s
not what we need in this world, we
need the function. There are many ways to
get function I think. Connectivity is the way that
Chemistry, it’s the metaphor for everything in
Chemistry, right? I mean, you got to get
units that aren’t connected, connected, and that’s
the message. In life, that’s the message. Cobble together proteins,
it’s pretty boring in a way, but its 20 building
blocks cobbled together, and that’s the message,
and that’s the verb, also the verbs and the message. Read off of the nucleic acids. So, the connections, this is a
great word, because, you see, it has a lot of things in it. It has everything we need, the
holy trinity; carbon, nitrogen and oxygen, and so it’s got
three of those, I like that. And then, it’s got S, could be
sulfur, actually SE is selenium, that’s got me tenure at MIT. Titanium’s in there too. But, but this is a pyramid that
I really saw coming on strong in the last few years. It’s the, especially
, three nitrogen’s, nature doesn’t use more
than one usually, and, but, for her connections, but,
and these we use sometimes, hydrogen like things, but
this is a magic place. I’ll tell you more about
it in a minute here. So, if we have reactivity,
that’s what Chemists should do. They should understand
why reactions occur, and how to get good reliable
ones, I think, that’s my belief, because the structure, you can,
you can’t get from one place to another, in terms of
new composition of matter, unless you can have,
understand reactivity. It’s, the structure, yeah,
you might want a structure, but you better know
whether you can make it in a realistic sense,
and that comes from understanding reactivity. And, once you get
the connections, you begin to have the chance for
new properties and functions. That’s the idea of
Click Chemistry. So, Click Chemistry is just
a way of, it’s nothing new, it was just, I had to
go back to before 1950 to find all the good reactions. There wasn’t anything after
1950, and I didn’t invent any of these Click reactions,
they were there, in the old German literature. You know, these guys didn’t have
chromatography, they didn’t, but they were good
at making compounds, and they took what they could
get, and they crystallized out, and they made a lot drugs that
way, they’re heterocyclic, so it’s like a Few Good Men,
you know, what can you do with a few good reactions? The Marines type of approach, and it sort of a Back
to the Future idea. In other words, if I don’t use
things that I can’t really count on in a pinch, then what
will I, what can I get out of that 10 years down the road? And, I think you have to think
down to the, back to the future, and Polaroid, I love Polaroid,
it was right around the corner from MIT, Lan was a genius,
that was a wonderful thing, I’m sure you remember
those, pull that thing, who would have ever
thought that would go away? It’s gone. And Kodak, are going to
[inaudible], they’re going to try, but, hey, I don’t
give them much chance. You, things change
in this world. You can’t have anything,
unfortunately, you can’t have reverence for
anything, you have to be ready; we do as human beings need
reverence for life, and we, and a lot of stuff, but we
just hang on to things too, when it comes to technology,
and how you can make a living, I don’t know if it’s, it’s
really able to have the kind of stability that we seem
to need in our hearts, so I’m looking for a no
nonsense way to make things. And so, what you’ll notice
about all this Chemistry, it works best in water. In fact, I’m going to, because
you guys are into the standards and basic things, I’m going to
tell you something about water that I think is really amazing. It’s not, we all know
water is amazing, but these click reactions, as
we did them over the last 5 to 10 years, we found out they
don’t only like water, they, the very best ones,
by definition, work best floating on water. Now, this is like
almost uncanny, because life doesn’t
use click reactions, she wants reversible chemistry. We couldn’t get off the ground, if we couldn’t recycle
the parts, you know, we eat other organisms, they
eat us, and they turn into, we turn into what we need
to turn into, and that, you wouldn’t have a
chance without modularity, but life is different than us,
and we don’t have much control. So, I was looking for some
really good reactions, bang they happen, but
they happen in water, and that’s great because
that means you don’t have to protect anything, you know,
like life itself, you can sort out everything, if you’re
allowed to use water as a solvent, then you can’t
have interference from amides and hydroxyl groups, so
here’s the idea, you just, this was just pure water,
heated for half an hour, and opens with buffered
[inaudible] and nice crystals, these aren’t explosive
or anything, you can just burn them,
they just burn normally, and then you put them
all in water for an hour, they don’t dissolve, that’s in a
[inaudible], and it goes click, and you got a nice solid, you just take the crunchy
crystals off the top of the water. And, what I like about click
chemistry, we kept on going on this, you keep
getting more material. You don’t, you know, it’s not, you don’t have any
chromatography’s, we just don’t allow
chromatographies until the end. We have three LCMS’s, because
everything is, no NMR’s, I hate NMR, I mean, NMR is
great, but, for mechanism, I don’t need NMR, I got the
structures, they’re coming out the way I, the molecular way
tells you the structure, okay? And the retention
time, and the LC, you don’t need anything
else with this chemistry. You got mad spec rules, and
that’s the paper that was, this is the manifesto, which
I think came out much better than we thought, we
didn’t have anything, all we had was some
ideas to use epoxides and use click chemistry,
strange things that bang, but very selectively bang. That was the idea. And then, oh, this is
for us, Philadelphia, three simple letters, but
getting them assembled in the right order takes
more than a good typesetter, even one of Benjamin
Franklin’s skills. Well, if you’re a physicist,
like a lot of you are here, you’ll know that, you know, you
can have atoms in a gas space, in deep space you can have
carbon atoms, and nitrogen and oxygen, but you can’t put
them in bottles and arrange for them to meet each
other, one at a time, so, it’s a very sticky part of
the periodic table, you know, there’s no empty [inaudible],
everything’s engaged, there’s just hardly,
it’s a real tough area, that’s why it gives
the stability to make life hang together, but it’s not easy
to put it together. And, here is my quick
course on stereochemistry, I’ve always liked it, the
MIT students seem to like, back when I taught
there, it’s always, this is the whole ball
of wax here, right? We have a point, the
carbon atom in deep space with a high vacuum, I don’t know
if anything, if there’s many of those out there, I don’t
think they can see those. They usually see things
like cyclic propene carbine in deep space, there’s, that’s
the major species, one of them, okay, so then we, we put
a bunch of them together, we get a [inaudible],
let’s just stop a one unit, and that’s the maximum state
of unsaturated, it’s a line, we then add hydrogens from
the, across the plane, and we can do it two
ways, we get a plane, then we add another pair
of hydrogens, and now we’re at the hydro-carbons, which we
get out of the ground and crack, usually crack them to get all
the things, but these are, this is now like popping up into
the three-dimensional world, and that’s the way I used
to teach how asymmetric, how you can get lots of
stuff from all of them. You go, you come
through this evolution to the three- dimensional world. And, if you look the pyrite,
something about oxidization, I was telling Bill, in his
office, just a few minutes ago, that I, I first saw, my father
was a surgeon and we went in Philadelphia Medical
store, and there was this book on the Biosynthesis of steroids. It was by Heffman
and [inaudible] and they already knew enough
to know, they lanosterol and cholesterol, you know, I
only had high school chemistry, but I could see that three
saturated methyl groups disappeared, and
they went off as CO2. Boy, that really caught my eye,
I just, and that, probably, may be the beginning
of my interest in burning things
and oxidizing things. So, as you pull out
hydrogens, that’s equivalent to oxidization, you
gain instabilities here. I’m just showing you the
game here from phenyl ethane, you just go to styrene and
take another pair of hydrogens who are the maximum degree of
unsaturation, I’m doing it here for [inaudible], and down here,
this would be a possibly made, but very unstable tri-
compound, but they’re known, especially they’re known if you
have, well that’s a long story, anyway, you start pulling
hydrogens out of this, you get here, this is a
known compound [inaudible], especially when that’s
another group, or group and then you go to the azide. So, what we see here
is the evolution of unsaturation growing in, and
reactivity is coming in too, and when you have, the atoms
being the same in a structure like here and here, they’re
very, very unsaturated, very stressed compounds,
unsaturation, almost by definition,
means reactivity, and yet, they’re really in a hole. There’s about 25 ways to make
azide, it may be up there, but it’s in a hole up
there, okay, a big hole. So, all roads lead to
azide in many parts of nitrogen chemistry. So that’s kind of really
something I think people didn’t realize is that it’s
so stable in many ways, especially the aliphatic ones. But, because they are made
out of the same atoms, there’s no big pol– bipoles, and there’s no big
charge separations, and so they’re really kind
of, not acid base sensitive, they’re stuck in a world
that’s highly endothermic, but it’s kind of like a cage,
and they have very few ways to go, that they can get
away from that unsaturation, that’s the kind of paradox here. So, they’re caged tigers, and
they only react, in a sense, they only react with each other. That’s all they really
know how to do. And, even that reaction you’re
going to see, is very demure, very very demure, except for
the ones that are activated, like the acetylene
dicarboxylate. So, we’ll come to that. So, here we have two entities, and not only are
they highly stressed, but they’re almost
invisible in our world. They are invisible in
the acid base world. That’s what life practices,
that’s where we live, so, this is the point that
I’m trying to come today, is the orthogonality
point of this chemistry, that’s what was a gift to us, we didn’t expect it,
we just ran into it. [Inaudible] edition of azide
and alkynes, this goes back to the 50’s, actually
this was first discovered, this [Inaudible]
formation, by Arthur Michael, he was at Tufts University,
he taught, he went Germany to learn, he did it in 1898,
in Germany, this reaction, of course, he probably
didn’t know, he was, he described the compound first, and it was definitely
a [Inaudible], and I thought that’s
kind of cool. He’s the Michael reaction,
and he was the first American that came back, he ended
up at Harvard, I think, and had Germans coming
over to post- doc with him. We all went to Germany
in the old days, I mean, everybody went to Germany. [ Silence ] It gives a mixture, and you
have to heat, that may be why, there are almost no uses of, [inaudible] dipolar
chemistry got used a lot, but not with azide
as the dipole, with more reactive dipoles
that were not orthogonal to the world, they’re, you can’t
use those in water and stuff. So, I’m going to talk, I’m going
to just start preparing you for what I’m going
to imply here. This is a perfect reaction in a
way that’s funny, you’ll see why in a minute, but the long
reach of a perfect reaction, that’s what I’m beginning
to try to see as the main, I see as the main
benefit of our quest here. And, here’s a case where,
whenever you have one of these reactions
that’s pericyclic, this is an [inaudible]
reaction, so it’s sort of like, [inaudible] they’re all
concerted reactions, so here this diazole carboxylate
picks the proton off the allelic and rearranges, and this is an
example from a few years ago, what this reaction’s likes . If you mix these together,
they float, density 7.76 for [inaudible] and this
one’s heavier than water, but they float overall,
so the color is from this and you see it floating on
water and then you stir it, there should be a stir in
there, and you, and it transits down to the, and if you add
more [inaudible] wasn’t right on this one, it will
turn colorless, and it will be 100% yield
of this white compound, which happens to be heavier. So, it transits through
the water, and ends up on the bottom,
and that’s not important, it could have started on the
top and ended on the top, or vice versa, I guess, it’s
not, that’s not the point here. What is important to notice,
is this same reaction, if you do it neat, so
salt, the same thing, float those same
liquids, now not as much, because these are high
boilers, and once you, once you get started and
things start warming up, then you can have an explosion,
and it will be a mess, but you won’t, it doesn’t
mean I want it faster, so we keep the temperature the
same in a bath, and these two, as liquids, without
water around, takes 70 times longer
than with the water. Not just this water
event, and they have to both be insoluble in water. If one is soluble, or if
they’re all in one phase with some co-solvent,
it’s not going to happen. What’s going on here? Well, here’s another one of it. We did it on a, like 50
mils, product 50 mils, just stirring it, each time I
stop, you see it going down, you just decant, it’s pure
product, and very safe, because this is a highly
exothermic reaction, like all click reactions,
but, if you’re going to do dangerous reaction, you
got, you can’t get in trouble when you have water around. Well, I won’t say can’t
, because some people get in trouble, you know,
there are ways to get in trouble, you know. Okay now, here, the best click
reactions are simple fusions, and actually, you
have to be a fusion to be a really perfect
click reaction. And, maybe you can see
why, if you think about it, it’s almost like,
Philips was telling me, he made a drink [inaudible]
today, for me to understand what
you guys do, some of you, and I was impressed, because I
think it’s really hard for me to understand physical
principles, but I do have a molecule,
I am a molecule, I think like a molecule, so
I guess, I guess, you know, that’s really true,
unfortunately. That’s maybe my secret,
I, anyway, this is the simple fusion, they perceive that’s
floating on pure water. Now here’s one, went up
to Edwards Air Force Base and got a couple half
gallon of [inaudible], I know you know what the, I’ve gotten into this high
energy community lately.>>[Inaudible Speaker Question]>>Barry: Yeah, its jet fuel, or, actually they have
different things that they, it’s not that great, I guess,
but it does burn very well, because it’s got all
this strain in it, and so they had considered
if for fuel, but you know, another thing it does
that’s really nice, you put it in the sun, see it norborandiene that’s been
photolysis with visible light. You put that norborandiene
in the sun, that’s cheap, out of gas, it comes as
a correcting product, and it cyclyizes
and then at night, you run it over a [inaudible],
or you can run it over any kind of [inaudible] catalyst
that gives up its energy, and you can run that
cycle around and around. Anyway, the reason
I wanted this, was because it’s been known, from one of my old Dartmouth
professors, Dave LaMal, that quadro cycline does
a two plus two plus two, it looks weird right,
but these bonds, this makes an addition
here that breaks, and you get a double bond there. It’s a very , it’s a
conservative reaction in very unusual territory,
because of the immense strain. So, if you do this reaction
neat, at zero degrees, you mix these neat, no detectable products
after two hours. But, if you float this on
ice water, which is say, make sure you’re at zero,
it’s done in an hour, and there’s 100% yield
with this product, which crystallizes
on the bottom. If you do it in homogeneous
phase, namely add a co-solvent, so these two are both
soluble, it takes a long time, and it’s always messier too. I, that’s the part,
you may end up getting, sometimes the rates aren’t
that different when you do it without the water, but the
product is always cleaner when the water is there. Every [inaudible] reactions
should be done floating on water, and that
seems strange, but that’s the truth
now, and I bet it’s going to take a long time,
organic chemists hate water, we hate water, you can’t imagine
how much a loathing we have for water, and proteins
and all these things, you know, in my generation. Here, floating, the
neat reaction of water provides a
thousand fold acceleration. Okay, now, I’m going to , I
know I’m probably not going to finish this lecture,
but anyway, now we go to Rudy
Marcus, Marcus theory, and one of his post-docs,
and Rudy’s about 81. We went to China
together last year. Two cities, and, poor Chinese
host didn’t get anything out of this, because Rudy
loved this on water thing, and we’re just like [inaudible], we couldn’t get away
from each other. My GOD, the guy is amazing,
I mean, he’s just like a kid. We had so much fun. Anyway, then he sends me
a paper, and I’ve gone around the guys like
Chandler, Burke, lots of smart physical chemists,
they just look at this floating on water and they see, microscopic systems don’t
interest them, I guess, because they don’t, I think
there was something missing here on understanding of water. It’s not that like the
Breslau In-water phenomenon, hydrophobic, it’s nothing, it’s
not that, it’s something else. So, and Engverts
and Holland agreed, and he’s the other great expert
on water, and Rudy admires him. So, Rudy sent me a paper,
about three weeks, months ago, and I didn’t read it right
away, because I was really busy with something else, and
I just read it a week ago, and that’s I’ve got some
slides, Rudy’s in Taiwan now, but his student sent
me these last night. And, so here, here is there,
this was an article by Engverts in nature, highlighting this
on water effect, so I’m going to give Bill these slides,
and a lot of other stuff, in case you want to
put it on your website, so people can have access to it. I, but here, this is another
version of this stirring on, here we have this mix, again, its red because of the chromofor
here, and then it, stirring, stirring, stirring,
and then it’s over, and this is Rudy’s slide
actually, and he takes the data from our paper, this
is [inaudible], I’m not the first author here,
I, well, I mean the main author, but anyway, this is Rudy’s
slide, and here are the rates, like [inaudible] and
homogeneous solvents, neat, so neat is 4.5 molar, in
this case, and for 48 hours. Now, on water, it’s done, at the
same concentration, of course, because nothing’s soluble,
it’s over in 10 minutes. And, another solvent
that’s not soluble in, like deuteron something
hexane I guess [inaudible], it’s not that, it’s not the
heterogeneous aspect that’s giving the rate of acceleration, and then comes the
homogeneous again slow, and, but if it heterogeneous,
and you have some ethanol, it’s still fast. So, Rudy was trying, I didn’t
understand what he was telling me until we’re all in
China, and then I got, now I think I understand it
better, and I’m just going to pass, I have the paper,
I’m sure he would be glad if I share it with
somebody, if they’d like it. But, what he did, I’ll show
you, this is an old observation. They’re so many papers on water,
and what its structure are at the surface, and this
is an oil water story, turned upside down, because
its carbon [inaudible], but this apparently papers that described what they
thought was going on, and mainly what happens
with water, at the surface, is it ends up protruding
naked hydrogen’s. It dangles hydrogens
from its structures into the organic phase. So, there is a, that’s an energy
cost there, because these are, are naked in a sense,
no hydrogen bond, and that’s what Rudy,
ingenious here was to see that, I think he’s really explained
this to me, to my satisfaction, and I don’t have enough
slides to make it clear, but I see all these spectacular
insights by Rudy, because, what he saw was that,
okay, if I go back here, he saw that you could
use, you could get, with, it also gets the biggest
rate accelerations when they’re hetero items that
are going to be in [inaudible], okay, so you can hydrogen
bond with these groups, and you don’t have
to pay for them. You see, if you’re in water, you’ve got to break
hydrogen bonds to make them to your thing, these are free, two or three free
hydrogen bonds, that’s the whole answer here. And, of course, it’s all
fast as hell, because it’s at the interface and it beats
the homogeneous reaction, so you have to realize
that the rates are enormous at the interface, okay, so that’s the way the
story breaks down, and here you can see,
what I loved about this, and if you’re students or
young, this is the kind of thing that a really good scientist
does intuitively, I guess, and a kinetisist, a reactivity
person, he said, “Okay, we’ve got to get all these
reactions in the same units.” So he made, you know, you
make a lot of approximation, so he put them all in big
equations, which I couldn’t, you know, look at, they make me
nervous, but they all came out, and he had these reciprocal
seconds, they were all in that, you know, they’re very
different reactions, but okay, once you have that, then
these were the experiments, the numbers, that
he got, that we had, and then his theory predicted
that, you know, he did theory, and so it’s pretty
good, you know, you see, it’s the basic fact of the,
where’s the acceleration here, it’s very much faster
on the surface, you see, very very much slower
without the surface. So, that was good,
and I loved that. That somebody could come to a
problem, that I’d been working on for three years, asking
everybody I could think of, and, and they just, and I
think it’s a big part of what enzymes are getting,
that extra kick, it’s a big part of the extra kick from water. We know water does a
lot of amazing things, but you have a lot of
isolated water entities inside of a protein, and I think
they’re doing you a lot more than we know. Namely, imagine those
free hydrogens dangling out that you can use, that’s
my, my message from Rudy. Okay, this is click
chemistry in the old days. This is where we started. These are all hot
things that will react. They’re all from strained, we
make these very strained things, pop them open with
nuclear clouds, so that’s what click chemistry
was, until around 2001, then all of the others
disappeared. One day I was looking
out across the Pacific and the terminator was
coming from behind, you know, and the sun was coming
up over the Pacific, Bill knows I’m weird, I work at
night, and I saw, I looked up, I said my GOD this
reaction is unbelievable, its out in the orbit
of the moon, it’s not even an Earthly
reaction, its invisible. Okay, it’s not very fast,
but it’s so invisible that maybe I can use
it inside of a protein, so I can use the protein as
the reaction vessel, and so MG and I have always worked, loved
talking about crazy things, and we walked on the beach a
couple of days, and we decided to commit a student, we did
it, and it took a long time, because it was much
more successful than we dreamed it would be,
and it was almost impossible, actually, for us to measure
[inaudible] or inhibitors, so. So, anyway, back out to
why you need this kind of, type of property, no reactivity
under terrestrial conditions. I mean, this is the ineluctable,
as Joyce like to say, ineluctable modality of the
visible, and Morrison, very, I worshipped that man at MIT,
power of 10, and when he, when we saw this for the
first time, from space, and NASA sent it back
from some probe going out, then we didn’t see any
turtles, or there’s no atlas down here holding
it up, you know, and there’s a lot
of water, it’s blue. We’re, people say green, I
don’t like this green thing, I mean the green thing
gets abused a lot, people say they’re
doing green, but hey, this is a blue planet, you know? Come on. It’s going to turn
green if we get, a billion years we get 100%
more sun, we’ve got to have, it’s going to be cool,
there’s going to be all kinds of things growing
through the ocean, it’s going to have to be green. Okay, now, this is the
mother of all azides made by, it’s been just made
in Germany by Banard and its blue as hell, right? It is scary, but, you
know, it’s really amazing, all these new cycloid addition
to asedaline, that’s a core, not something I’m going
to work with though. Anyway, this is a glacier
we got to walk on illegally, because the young guys were in
charge of the zodiac I was on, and this is in Antarctica. [Silence] Okay, I called it azides, and this seems a little bit
weak, I’m going to get my. [ Silence ] Learners got 20 of these
he bought that are wired to be 10 times more powerful,
50 amps or something. This is, I don’t know,
Learner doesn’t do anything on a small scale. Okay, this one is
just a normal one. The, could things
get much worse, well, what do I mean by this? Watch what I’m trying
to say here. The [inaudible] cycloid
addition, and Roth [Inaudible] saw this,
when I came over there, I said, and I showed this lecture about
the [inaudible] inhibitor, he said, “Barry,
you’ve got a problem.” He’s 86, sitting out there in the audience,
and I said, “What?” He said, “I can give you 20%
of your rate [inaudible].” You know, holding
things together, where do you get the rest? And he was right,
and so, look at this, it’s a very exogamic reaction,
and its about 70 kilocalories, but delta G, but I guess,
about 50 to 60 delta H, and a lot of heat comes out,
and, but it’s very slow, and at micro molar
concentration, now we’re going to incubate the pieces with
an enzyme, the enzymes going to bind the two sides, and then
they’re going to hold together, it’s going to go
click, that’s the idea. But, it’s micro molar
concentration right, because we’re dealing
with an enzyme, at micro molar concentration,
we measured the half life of a typical saturated azide
and saturated asedaline, and we backed off to room
temperature from 100 degrees and with an error of plus
or minus a hundred years, it’s going to take
three thousand years to reach half-life. Well, I mean, if Ramsey’s the
second and Egypt started this on the Nile, we’d be getting
half-way there now, so that, you know, this is kind of
like, I’m learning around here, [inaudible] everybody
speaks [inaudible], well this is a long
time too, and so, how can we possibly get
anything good out of this, well, that’s what makes it so good. In retrospect, if it was, the
more demure it is, the better, the more information you
get, when you see it, this trace of product
[inaudible], and so we [inaudible] think
is the fittest click reaction, because it’s invisible,
it’s stealth chemistry, they’re alien groups,
they move invisibly through the terrestrial world
that we live on, the surface. So, it enables, this orthogonal
is a big word for me now, and it’s actually a word
that tracks inside finder, which doesn’t have any
math in it, so I don’t know where you look up
incidence of math things, but orthogonal is obviously
used by mathematicians more, but it’s coming up in chemistry,
every year since the 60’s, and you know, when you put
in one word and search, then you count the frequency,
there’s no, there’s no, no years out of order,
it’s just coming up. We need orthogonal
things, because, we’re pretty blunt objects,
when you think about it, we’re big blunt objects,
we’re trying to do chemistry, we’re trying to do a lot of
things and we need tricks. [ Silence ] And so, the idea was we use
this enzyme, [inaudible] raised from an eel and hijack it
and use it to defeat itself. And this was a paper
published, cover, this is that electric
fish, he has a whole, like mostly like fish, they have
banks of [inaudible] enzymes that produce these
massive discharges, and so we’re using the
enzyme from sigma and used it to incubate pieces and see
if we could get a bond, and if you look at the, well,
why would we want to do this, and I try to explain it already,
but we wanted to do this by, to use the enzyme to
tell us something. Give us some whispers, some
hints about what it likes, because we always, before, chemists make a finished
structure, they look at it, you know, they polish
it off, you know, they connect everything, and is
it stable in water, and okay, good, we put it, then we
just put it behind the veil, as it were, and ask,
“Does this do it for you?” And, a lot of cold
answers come back here, there’s too many compounds here, let the enzyme do
the last step, okay? That’s the idea. It’s a pretty simple idea. And, it turns out, we got
a Cinderella, or Princess and the Pea result, the
thing didn’t just whisper, it shouted at us, because,
anyway it’s a Trojan horse idea, but it’s a little
better than that, because you just leave the
pieces outside the city at night, and they take
them in, and they can’t get out of their rooms in the
morning, everything’s locked and you can run in and
take over the city. This is a picture of the enzyme
of the mouse, with different, these are x- ray pictures
from which things are removed. Either it’s empty,
with water in there, but see this [inaudible]
pod here that’s coming out? This is about three
or four kilocalories up the energy surface of
the enzyme, it’s [inaudible] of this enzyme, it’s
[inaudible] 286. If it’s not there, you
don’t have a [inaudible]. The searing’s at that bottom
of this hole, and this one, apparently, guides the
quad, you know, cooling in, and you’re going to see that
this one is what we discovered with this in seafood, that
they didn’t know existed, and they now think it’s an
important gating confirmation for the protein. So, we go fishing up and down
the hole, this was known to bind on the outside, this
is not a drug concept, because that’s [inaudible]
compound, but this was [inaudible]
just blocks the hole, this the takrin piece,
that had been a drug, binds down in the bottom. [ Silence ] And, we went fishing with
about, well, permutations of these pieces, we put the
asedaline sometimes on that, we put the azide on,
different lengths, obviously some can’t reach
down into the gorge, middle, to make the bond, and these
were the two that hit. Others, more sensitive
machines later, four years later we found other
hits, but they’re all exactly, always this piece or you can
also turn the thing around and put in asedaline here
and azide coming down. But, this was the major
obvious hit in the beginning, and if I show you how, we
got the x-ray eventually, and so we’re going
to go into the gorge, we’re going through
the structure, this is this long gorge, it’s
full of aromatic amino acids, and here comes the takrin
labeled with an azide down, and this part is simulated
to match an x-ray structure, because takrin has been x-rayed
many times inside its place, so now we’re sitting down
here where takrin binds, and here comes the alkynes down, and now you see them
juxtaposed here and it’s going to snap together, oh,
it’s too fast, oh. What I was, what I wanted to
show you, and I don’t have time to do half of what I think
I should be doing today, so I’m sorry, I’ll try
to, no I have to go on, we can come back to it. If we publish this in PNAS,
when the x-ray came out, took them a few years to get the
x-ray from [inaudible] Bourne in [inaudible] a husband wife
team in France in Marseille, and this is the anti,
what it turns out is the tryzole normally
goes this way, and this way, the homolomo controlled
cycloid addition is more or less degenerate in this
case, so it really can’t pick between the two, so that’s
cool, I thought we were going to get some tinplating,
you know, if the enzyme is around this, it’s going to
go this way or this way, but not a mixture, and sure
enough, we did get tinplating, we got only the scent,
but the anti also forms and it’s a five hundred
[inaudible] molar inhibitor, but it does nothing unusual. This is the way every x-ray
structure had always been for the gorge mouth. Whether its empty or full,
the tryptophan is in the wall, tyrosine is in that wall,
and so this is the anti, which the enzyme didn’t make. Here’s the [inaudible], it had
ripped this out of the wall, and changed a lot of other
things, and it was now stacking on either side of the pi
system of [inaudible], and the main thing is, if
I pull out the inhibitors from the x-ray, you can see the
holes are very different here, even, well, down in, the searing
down over here behind that area, what I wanted to say was, that
when the inhibitor is in, see, what people don’t get, of course
[inaudible] did right away, and you really need to
be a physical organic, physical chemist, or
physical organic chemist to understand reactivity, and
[inaudible] saw it right away, well, you know, this thing
made it, this excursion, it’s probably less than a
percent in this confirmation in, this confirmation is estimated
to be 3 or 4 kilocalories at the energy surface, so, you
know, you’re not going see it by [inaudible], it’s going to
be less than 1% population. So, what happened is, these
two, these three things, one big molecule, two little
ones, the azide and asedaline, they took a journey up the
energy surface, and they got to this place, they
didn’t know about, the enzyme certainly
didn’t know, it’s a closet tryzole
synthesizer of the first magnitude,
it does a great job of equalizing the dipole and
everything and make the tryzole, but then it’s stuck, so
its, we call freeze-frame, so you have the energy, you see, [inaudible] you can’t
get much information out. But if you have a dart,
you know, it’s like that, what’s his name, oh, Muhammad
Ali, float like a butterfly, sting like a bee, okay, this
thing is so demure, but boy, once it goes, it’s gone,
it’s gone, so you nail it. So, we found this high
energy confirmation that way, and it’s happened only,
oh, and then we went after, the med fly is a problem
right, and also mosquitos, and couple other students
who have left the group are in academic jobs, they’re
going after the med fly and the mosquito, with various
selectivities, because we’re, all the vertebrates have
this open, very similar, almost identical structure. All the insects, they
diverged early and everybody with a nervous system needs
this enzyme, even a [inaudible], so it’s everywhere
in cellular things. And, the fly chooses
to make this one, out of these same pieces, it’s about a thousand times
difference in toxicity, hopes to get something a
million times different and then maybe you could
use them as insecticides and this is the fruit fly,
which we got the enzyme from France too,
from another group. Well, this approach has worked
on 20 different proteins, some on industry,
others, that I know about, and I think it’s really catching
on, and I have a pet scan, I have a high through, it’s
become high throughput, thanks to Art McKolba
[phonetic], at UCLA, and at Siemens, and I could
show some slides at the end about the Pet Scan, which
is just unbelievable, how that works, but this is just
a HIV example, and we see here, [inaudible] doesn’t
have to be massive, this was a mutant protein that
we’re working on at Scripps, a mutant HIV protein,
protease, also, this woman is [inaudible] is in
[inaudible] lab, and they work on transfer RNA and RNA a lot,
and just managed her husband in my lab, and they got a hit
with the plasmodium trans, the RNA piece, because we,
this is for tryptophan, and tryptophan in
mammals, I mean, higher animals is
not edited beyond, it’s just a weird amino acid, so evolution ablated the reading
frame that tries to check if it has the right loading. So, but the plasmodium
still has a checker frame, and they got a hit by, I’m
not going to stop on this, but this just to show you the
range, it’s very hard targets when you’re dealing
with nucleotides, but they used a nucleotide with
an asedaline and ran azides by it, and they got a
selectively made selective inhibitor for that,
over this, that’s human. This is a team. Palmer had made it all
possible in [inaudible], they can measure [inaudible]
molar, and even they gave up on atom molar, because we’ve since easily gotten atom
molars inhibitors [inaudible] and you just don’t, you
can’t get them off anymore, it’s like 26 kilocalories
of binding energy, and so, there’s just no way
you can measure that by modern methods,
according to them. This is, the guys, this Warren,
he’s the first student from MG, and there’s my student, now in
England, post-doc at the time, and he’s the modeler, poor guy,
modeled, they model like crazy, but every time they
modeled everything, they got a different structure, but then enzyme structure
comes in, guess what? It’s totally different
of course. Nobody could have guessed
that, but the model, I don’t have much, I love
modeling for mechanism of small things, but
not for, not right now for this monster molecules. So, I’ve gotten away, not good. This okay? Cal, who’s going, I had to
put this up, I usually put it up in reverse, because
what’s going to happen now, if I talked about copper first, I would have had everybody
thinking there was copper in that enzyme stuff,
there’s no copper. This is the pristine
[inaudible] cycloid addition, and very pathetic reaction
in the sense of rate. But, now, what’s
going to happen, we’re going to discover
something, almost the next day, thanks to serendipity,
because we needed now, oh we’re getting these
hits, we have to try to make [inaudible] we wanted to
do that, so we started, I said, “Throw some copper in.” Luke threw copper in, and
from the very first moment, the copper accelerates
the reaction over a hundred million times. It may be a billion
times, I don’t know, it, there’s so little of it active that we can’t really get
a handle on it totally. So, here comes the
copper, and it was, remember this very slow
reaction, and you have to heat it for 24 hours at
120 degrees to get these, almost neat too,
very concentrated, and you get the one to one,
and it’s at the strongest link, and it, how could
we like it so much? Well, this is the
serendipity of click chemistry. It started with the
[inaudible] idea, right, because we’re looking
at simple chemistry from the old dark ages, and
I notice something about it, and then we’re keeping
things simple, that old KISS principle gave us,
suddenly ran head on into the, and this works really better
that we thought, then comes, we got water, that water
thing is interesting, I think, and then comes copper, and this
is the final thing I’ll talk about today, but this is
mind-boggling reaction for the same, for
different reasons than what you might expect. I’ll try to tell you a little
bit about it, and then, well there’s many more things
coming down this list now, I just, this is the
original trinity of breaks that came very quickly
after the first idea here. And, how much reactivity
does a chemist need? This is like that Tall
Story, Short Story, How Much Land Does a Man Need,
which is one of my favorite, it’s a morality tale [inaudible]
large, and I recommend it, if you haven’t read
it, but I think we, think we need infinite
reactivity, or we need more and more fancy, but no, I think
what we need is something that’s orthogonal, I mean, we need
more and more orthogonal things, and you’ll see, you’ve
seen one reason for that, let me show you some more. [ Silence ] Valery Fulkin came in,
because he’s, he was a, died in the war click chemist,
he’s an Associate Professor at Scripps, and he’s going to
be independent before long. He and I said, “My
GOD they won’t.” When Luke Green discovered
the copper reaction, he was going back to England
the next day, and he had it in organic solvents and
we tried to get it out, tried to get the
next [inaudible], who was a really good
chemist, but wanted to stay in organic solvents, and
Valery, and I said, “My GOD, this thing needs water,
right, I mean, yeah.” And so, so Valery went, put it
in water, and didn’t even have to put copper in in
the right one form, it’s got a copper
oxide coat on it, so it recruits its own
copper, its [inaudible] and then it starts generating,
once it gets started, it’s just about 3 parts
per million copper that did the reaction in the
solution, and it crashes out. Now, I could tell you
the mechanism of this, let’s see if I dare do this
now, let me exit it a second. [Silence] What’s just going to come up? [ Silence ] And, I probably messed
everything, can I open or not? [ Silence ] This, or just, if you’re going
to ask about the mechanism, I should, I wanted to show this. There are two coppers involved. We did the kinetics,
one post-doc, one graduate student
lived inside of a dry box, I didn’t do this, this is all
MG, Fen, and Valery Fulkin. And so, the kinetic’s absolutely
clear, there are two coppers, and that’s a critical point. But, other than that, it’s
really hard to tell what’s going on here, because the copper,
it’s so active when its working and we’ve got two
more papers coming, they’ve got two more papers
coming out on the calculations that are really proving,
beyond any doubt on how good the calculations are
now, DFP, but see, the azide, this isn’t showing the
whole thing, we have, this is the last part of it, you see where the
reductive elimination occurs, and we definitely know it’s not
a cycloid additions directly, and this barrier
keeps going down, every time we find a new
way to deal with the copper, the second copper,
and, I’ll just go back. [ Silence ] So, it could, well, really,
we usually make the copper in [inaudible], copper sulfate,
and scorbate to reduce it, copper 1, and Valery, about
a week later, he went, he has a friend, a nurse,
over in the hospital, he got, this is not legal right, but he
got 10 cc’s of his own serum, blodd, and he centrifuged it,
that thing goes better in serum, okay, this is strong
inference, I’ve got to give you that article, I mean, some
people might have taken 5 years to find out it worked. Valery is really good, and this
guy has got strong inference, he’s tremendous creative
mind, and he also, when he smells ether, its yellow
and ethyl acetate is blue, you’ve got to have a
little mixed up stuff, you know, to get any ideas. Okay, so then we go one, that
was the first publication, and Sava, and Luke and Valery, and it’s really Valery’s
reaction, in my opinion, in the sense of showing how,
how robust it is, now just, this is Valery Fulkin, and
MG is the father with me of this [inaudible] and Hart
McKolba has been, off and on, in my group for so many years,
and he’s coming back to Scripps with an adjunct appointment, but
he’s CSO of a startup company, the Pet Scan thing, and
we’re the click amigos. And this is Valery’s graduate
student here, no, no, I’m sorry. Valery was in China, and,
because one of my students, Pong Wu, is a famous, his
grandfather is a famous teacher in the town where the bears
come from the Polar bears, so anyone of us, who goes there,
apparently has privileges to go into the secret area
in the back, and so there’s 30 bears back
there, and there all looking like there not on the evolutionary
survival rungs here. How the hell these
things ever lasted when man came around,
I don’t know. So, okay, then I, just to
make sure copper was okay, I had to go to South America to
visit this mine in the desert, and that’s copper sulfate coming
out of a leaching process for, 20 years it been running
out, and they take it and electrolyze it, oh, I
wish I could show you that, I couldn’t find the
right slides last night, but it’s a huge beautiful
place, it looks like artwork, and so they take
the copper sulfate, and in 20 more years
it will run out, then they’ll go to
another location. And, that Victor Marten, he’s
number two man, he’s like one of the Godfathers of the
asymmetric epoxidation, he and [inaudible] are
bosom buddies and they, he’s in the Canary Islands now. Okay, “gold,” this is Kipling,
“Gold is for the mistress, silver is for the maid,
copper is for the craftsmen, (or the chemist maybe,)
cunning at his trade. But, said the Baron,
sitting in [inaudible] iron, cold irons, master of them all.” And, I love that poem, but
let me show you some copper. I brought it here because
I get, we get these in 300 pound buckets,
and I’m running low now, so I have to get some more, but since you’re the National
Standard something or another, you got tell me,
you got to tell me, these are electrolysis
anode copper balls, you just throw them in,
you know, your plating that you’re dumping in, and this
is supposed to be, I forget, there’s three different sizes,
and this is an exact number of moles, but I just wondered
if you have any balances around, of course we could
weigh them on, but actually I think I’ll
just pass them around.>>[Inaudible Speaker Comment]>>Barry: But, look at, but look at how beautiful
the crystals are. See they just poured
into a sphere thing, and the crystal’s
unbelievably nice to look at. [ Silence ] Anyway, people, I give them
out to friends and everybody, anybody that wants them, because
they make great paperweights, and it’s very pretty
metal for its price. Okay, I think I better get, and
then, this, since I’m impatient, when I, we got this reaction,
it was a couple of weeks later, I said, “Lets glue
something together.” So, this is two, once
inch copper plates with about 80 kilos hanging,
70 kilos hanging on here, and it’s got, it’s been
glued, see, this is the glue, it’s going to be a polymer
made by the copper itself, you have steel, it still
water the next day, but If you have copper, and it’s
going to make this nice glue, and it’s still very clear,
the metal’s very clean, I was thinking somebody in
the Navy should be interested in this, because I had to
paint a lot of copper on boats, as a kid, and they
really make a mess, I was just thinking maybe
this would be a good way to cover boat bottoms. This is the way we
did it the first time. We took, this we have about half
a kilo of it, it’s very stable and easy to make, and
it’s almost impossible to stop accolading ammonia,
so you easily get to try, and you put those together and
just let them stand overnight or heat them for 30
seconds at 50 degrees, and you’ve got a permanent
bond between the copper. And, there’s a couple
more papers on this, if you’re interested in
material science things. And so, here we have this
reaction; 26 kilocalories, right on the money,
calculated or measured for the cycloid addition,
over amount concerted, okay? We’ve got 26 thousand foot peak,
and with the enzyme hugging it, it’s brought down on the
order of weeks, maybe a year, it doesn’t really get as far as
you think, because all you have to do is see that
little blip in the LCMS. You’re only making one
tenth of one tenth of 1%, when you can see
it, so it’s going to take almost a
year still to finish, but if your enzyme doesn’t
rot, and so, but down here, this thing is just
something else. And, I’ll just, it
makes [inaudible] and there’s my students
who worked on that, they’re in Kyoto Japan,
couple of years ago, they were giving talks, and
works inside of an animal, I mean, inside of a
cell, it even works, because there’s copper in there, but that something I can’t
tell you too much about today. But, Ben Kurvate is making
lots of protozoan work, and you go in with a
accolading agent for, and he went to specifically
hit a brain protein, sacrificed the rat, has an
[inaudible] hanging out, which is very low tech, and
not going to cause any trouble, then he takes the protozoan,
puts the azides and copper in, and attached the
florescent agent, and runs the electro
[inaudible], and you can see, it picks it up. It can find a needle inside
of a needle in a haystack. There’s no way it’s not
going to go, and it’s almost, it’s quantitative
reaction all the time. It’s like a, it’s like a
polymer grade reaction, right, you can’t may polymers,
there’s nothing new to the polymer world, but this
is different than a polymer of the normal kind, because you
can have anything hanging on it. No functional group will
stop it; [inaudible], it goes from Ph2 to Ph,
let’s see if I can get this, well Coleman sent a lot, I’m
going to give you these slides, so you don’t , the hydro gels,
it makes great hydro gel, Haucker is one of my heros in
this area of material science and he’s done some
beautiful stuff. Coleman’s making, putting
things on narrow, nano wires, it attaches things to
virus, this put on 60 things onto a virus, and you know,
people are really happy with it, because it doesn’t have any
times when it won’t work. So, why did I say alien? Well, it’s alien because
the Ph doesn’t matter. I mean, you can go
from Ph2 to Ph14. Temperature doesn’t matter. You can go from minus
20 to 300 or whatever, but a lot reactions
would probably do that, but does it always
give 100% yield? No. There is nothing, the guys are
like, true love waits, you know, these guys, they don’t
decompose, you know, they don’t do anything
until they react with each other, it’s uncanny. No functional group, we’ve
done reactions 40 linear steps, 96% yield overall. That’s what MG has done. Now, here’s something I wanted
to mention, because Chris, well, you must have some use for this. I was thinking of patenting
this, because I just, we got a couple liters
of this solvent. This is the [inaudible],
I thought, no, there’s never been much around, but they’re now making
[inaudible] or [inaudible] inhibitor
with it, and it’s starting to become available, and there’s
no reason why it couldn’t be reasonably available. And it, people always
thought when I saw tryzoles, the guys in Farma,
Narvadius and Merck, oh, it’s going to blow up, you know. The tryzole, well the tryzole
so bloody stable, they’re, benzyl tryzole is more
stable than natolyne, but look at this,
here’s the DSC. You come out with this, it’s
a liquid, at room temperature, 23 degree melding point, it
tastes sweet, crickets love it and they go crazy for a
day and then they die. I mean, you know, things
like that, I’m sorry, you can do that kind of thing,
because they’re going to be fed, you go to the store and
buy crickets, but other, mammals don’t like it too much,
we injected it into some mice, and I’ll tell you, if you
want to know what happens, here is the endoderm,
big heat capacity, much bigger than
water, about 200 degrees where it boils, it boils at 203. So, I figure maybe you can use
it for a heat exchange, right, heat exchangers, it
stabilizes copper, it stabilizes metal surfaces, so it probably would just
be great inside a contained, heat conducting, transfer
system, and DSC was, was the measurement was stopped
by Navardius at 300, nothing. And, if you go to the microwave,
oh, I didn’t add the microwave, I guess, oh yeah, I did. Here’s pure water over
here, at 20, at 210 degrees, 20 bar plus, [inaudible]
pressure. It’s between zero and
one atmosphere at 210, I don’t know why its
[inaudible] boiling point, but you see this increase
in the mole fraction, this is pure tryzole,
and this pure water, so it goes up much
faster than water. It goes up like a linear bullet to the 200 degree
mark, in the microwave. So, I think this compound,
and it dissolves proteins, you can heat the proteins in
it, they don’t, they denature, but they don’t crash
out, it’s weird stuff. [Inaudible] C, it dissolves
in it, without losing any of it copper or its iron,
I think it’s interesting. And I just, what was the other
thing, oh, and then I found, recently at Georgia,
this is interesting because I know you people
like, well fuel cells are going to have to have some, get
better and better in this world, and if you take [inaudible] and [inaudible] this is a very
read ups, much more sensitive than this, so these,
this [inaudible] and his colleagues
made polymers of these, and this a hundred thousand
times more conducting with a little acid in
it than the [inaudible], and the reason is, it’s a
[inaudible], for [inaudible] to transmit, it has to
turn over, tryzole doesn’t. It can use the slippage to the
two nitrogen, and they figure that must be the reason. Okay, that’s alien, orthogonal,
it’s finished, there’s, oh the high tolerance
of click chemistry. This is from Craig’s lab. He’s from Australia,
and you know, tolerance means you’re
not an alcoholic I guess, but she’s not, she’s an
undergraduate at Stanford, was working in his lab. Craig’s now an academic
at Santa Cruz, and I, I can’t say enough good things
about him, you’ll love him if you get him out
here for a lecture, and there’s my co-workers
and I’m overtime, I tried to mention them
anyway as I went along, so, that’s it, thank you. [ Clapping ] Well, thank you Barry,
I think you took us on a journey there from, so
that we might understand a lot of the things that
you’re so excited about. Let me open the session today
for questions from people. Got some chemists out there? Yes sir, right in
the middle, yeah.>>[Inaudible Speaker Question]>>I work, actually, we’re
connected to Boulder too, so if you could shortly
repeat the question, so they can hear us in Boulder.>>Barry: Okay. So, my cells, I,
actually, yeah, it would. You got to remember,
see the simplest azide and asedalines are slow,
but you can activate, you put some liquid
on [inaudible] groups on the asedaline, and
you can raise the, or activate it quite a bit. You saw the dyethylcarboxilate
reacts at quickly, so yeah, you, in a biological system you
can’t afford to do that, because [inaudible]
inside the [inaudible] and it’s a good [inaudible] as
well, so we do a micro addition, but yeah, I, well Chris was
showing me today how he drove holes in the sides of, I mean
I could see a lot of cases where you could suture your
assembled vesicle together with the reaction, especially if you had copper
in there too, right? Because, and you wouldn’t
have any problem with that, I guess you could have a
little copper, couldn’t you? But, I know where you
want, you want the vesicle to have a rigid structure,
or not? Is that what you’re asking?>>[Inaudible Speaker Comment]>>Barry: Oh, oh, [inaudible],
oh that’s a good question.>>[Inaudible Speaker Comment]>>Barry: Okay, now, what
happens is that we get a lot of the tests, those tests
you do, like add [inaudible], add the, you add a
[inaudible] to the water on a water phenomenon,
and you kill it.>>[Inaudible Speaker Comment]>>Barry: Yeah. You, you’d take it
down, yeah, not good. Because, you see, it makes sense
that it’s not good, because, well, its, I guess, maybe Marcus
and Ingrid’s would explain more, but it’s different, it’s this
thing, the water phenomenon, of course, it’s just another,
a totally different story in a way, but I, yeah. The cycloid addition is very
slow, unless you add the copper or unless you, we’re not making
an, see if I had an enzyme like this, and I put the pieces
in, it’s going to take a year to make it show up
as an inhibitor, because there’s nothing there,
it taking so long to make it, but it’s the power of
analytical chemistry today, you only need a little tiny
blip, I could show you the, on the Pet Scans or, Hart
McKolba’s now go this on micro [inaudible], where he
can do 200 enzymes at a time, and it all gets mixed and put
into chambers, you shoot it on the LCMS, and get the
same result as you do on the [inaudible] tubes,
and, then he puts [inaudible], and shoots it into the rat, gets
real time [inaudible] kinetics, and sees the whole thing light
up where it’s supposed to, and sometimes it’s
really available in the cells I was
telling you about, but it’s like [inaudible],
it goes in the cells, stops [inaudible] gland in E2,
it looks like it going to be, after we shoot it in
the rat, it never gets by the liver [inaudible], it’s in the common bile
duct in 20 seconds. You need to know these things. People, I mean Hartman’s doing
this, he gets all the inhibitors down to an animal, or molar,
or pekoe, he shoots it with [inaudible], it’s a go or
no go in six weeks, and this, this is, that’s why I like
this stuff, I want to give you that tape, anybody who wants the
Pet Scan stuff from [inaudible], it’s got movies in it,
and it’s all about cancer, they started off with
cancer diagnosis, but it’s a drug discovery, it’s a radical new drug
discovery method really.>>Okay, I have a question too. Can you say anything
about the connection of the click chemistry to
the common [inaudible]methods that are so prominent in
the drug industry, I mean, does this fit right
into that, in?>>Barry: Yeah, well, I,
what I find, there’s, the reality of what they do in
Big Farma, is they love numbers and they get ready and they
screen for three months, and they can’t stand
false positives, I could show you half
a dozen case studies where we just made one
plate, and we made the, [inaudible] little copper
involved, we made it right in the [inaudible], and it was against the [inaudible] the
last step in [inaudible] or, in other words, [inaudible]
inhibitor and nobody knows why
they work, but we got one that was 400 times more
potent on the first plate. Now, if I have another azide or
asedaline left on it, I go down. But I don’t go down for long, if
the thing goes through the rat and doesn’t make, you know, I throw it away, I
take another one. They don’t do it, see in
Farma, they got all these, they’re too intentional,
and there’s no diversity in the Goddamn molecules, they
start, excuse me, but they, you know, they’re made, they’re
going for a number, so the, just the connectivity
makes a difference, right, that 10 to the 63, you
have, you start to realize, in one universe, Hartman has a
slide, where he shows, you know, we’ve got this one universe, then we have the Hubble
Space Telescope view, and we’ve never even been
in these other universes, and they’re all possible
[inaudible] containing, they don’t have any
reason not to, it’s just that it’s
not our world so far, because we connect
things, you know, the Devil’s in the details.>>Any question? Yes. Okay, [inaudible].>>[Inaudible Speaker Question]>>Barry: I don’t think so. I think life always was facing
water, as the main team, and in the beginning she was,
she was dumping her electrons into sulfur, not into
oxygen, mainly, or into iron or something, but she did need
that, she needed that something to push things, but she, the
reversibility really strikes me, whatever was before life,
and that would be before RNA, before anything, I mean,
RNA, there had to be some, in my way of looking, there
had to be something building up there, unless the
[inaudible] things, it happened on a deep
ocean trench on a rock, and [inaudible], I mean
the rocks have, you know, you don’t need the
membrane right away maybe if you have rock, and
maybe we’re all related to the same rock, I don’t know.>>Life formed from a rock. Any other questions? Yes?>>[Inaudible Speaker Question]>>Barry: Ah, good question.>>So, the question is
why copper, is that what? Why copper and not
silver or gold?>>Barry: I don’t know,
I was trying to think of some metaphor, this copper
thing, because that was so.>>Back to Kipling.>>Barry: Oh, what?>>Back to Kipling.>>Barry: Yeah, back
to Kipling, yeah. But, silver, you can make
the silver asedalide, and they’re stable, it sits
there, nothing happens, I mean, I’ve been explained,
by my friends who are real heavy duty
organic metallic chemists, but copper’s got, it’s the, it’s
a very simple element, you know, once you get the copper 1,
it’s got that asedalide, it’s going through the copper
asedalide, I don’t know if I didn’t show
that properly, but, and that’s basically taking
care of everything it needs, because now it, it’s not a
filled shell, but its D10, and silvers the [inaudible],
they can come out, see the [inaudible] have to come
out and engage in a funny way to make an [inaudible]
intermediate, and they’re just much more
stable; silver and gold. You can make the asedalides, but
the [inaudible] aren’t in play, where they have to be,
and the exchange of rate, the greater exchange
of things on copper, that’s these [inaudible]
that are around, I bet you there’s nothing,
everything gets shed, I think, because you can, we need
[inaudible] to stabilize in the biological fluids,
but that’s just a place where the copper hides
when it needs to, to not become copper 2. I think it has to
get out of there, and it’s just the [inaudible]
complex, and exchange rates of water on this
are almost the same as on sodium, diffusion
controlled. Copper is slippery as hell,
I mean, if I measured copper in your, some part of your
finger, I’d know the occupancy of everything in your
body, it’s an equilibrium. In the old days, for bacteria,
when the sulfur was around, one thing that will stop
it is sulfur and cyanide, not permanently, but it
will just make insoluble copper sulfide. So there were pro, there are
carrier proteins for copper, but there are, they’re
left over from evolution when the Earth was
[inaudible], that’s my opinion. But [inaudible] at Northwestern,
has show copper is, it’s a pool, and it’s you can’t
keep it anywhere, it just, it goes everywhere. Does that help? I, that helps when
you’re slippery. I mean catalysis really
requires slipperiness, I learned that from Osmium. Osmium you’ll never
hold onto that element, and I don’t think I
don’t have any plans, I’m trying to make a house
so they can have copper stay where it’s supposed to, inject
it into veins and it goes around feed strips of
azide and asedaline in it will chop off plaque
or something, a little motor, but you know, how
to contain copper, I just don’t think we can do it. Not right now, I don’t know how,
and maybe it’s like that song, what was it, the answer,
no, it’s another thing, no, that’s my answer to you.>>Okay, if that’s
the last question, let’s thank Dr. Sharpless
again for coming.>>Barry: Thank you. [Clapping]

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